This proposal builds upon the database, specimen repository, and preliminary findings from our ongoing Ecogenetic Study of Lung Cancer in Minority Populations (RO1 CA55769). This case-control study in African- American and Mexican-American men and women integrates epidemiologic data with cytogenetic and molecular markers of susceptibility, and is based on the theme of interindividual and ethnic differences in susceptibility to tobacco carcinogenesis. We will extend the study (from a projected 150 African-American cases and controls and 75 Mexican-American cases and 150 controls) to accrue 400 additional lung cancer cases of all ethnicities and 400 sex-, age- and ethnicity-matched controls prospectively identified. Using the same study protocol, personnel, and data collection instruments will ensure comparability of the data across both phases of the study. Our Specific Aims are: 1. To assess tobacco mutagen sensitivity by quantitating the chromatid breaks induced by in-vitro exposure to bleomycin and benzo-[a]-pyrene- diol-epoxide. 2. To evaluate DNA repair capacity after BPDE exposure as a risk factor for lung cancer using the host cell reactivation (HCR) DNA repair assay in the newly accrued cases and controls, to compare with the mutagen sensitivity outlined in Specific Aim 1. 3. To test the hypothesis that the in-vitro induced chromatid breaks are not randomly distributed, but affect specific chromosome loci, using cytogenetic (Q-banding) and molecular chromosome painting) techniques on tumor and normal tissue. 4. To estimate ethnic-specific genotype frequencies of cytochrome P450 CYP2D6 and CYP1A1 and glutathione-S-transferase (GST) mu and theta (funded by E50671 7, PI-Dr. J. Wiencke). 5. To correlate levels of smoking-related DNA adducts in DNA isolated from the lymphocytes of a subsample of cases and controls by 32P post-labeling techniques with smoking status, mutagen sensitivity, DNA repair capacity and metabolic polymorphisms.